Although ethanol is commonly regarded as an anxiolytic, its administration mimics many actions of stress that involve activation of the hypothalamic-pituitary-adrenal axis (HPAA). An understanding of the effect of ethanol on this axis requires an appreciation of the central and peripheral regulatory factors and their interactions, which constitute the HPAA. Intimately involved in the homeostasis of the HPAA are several neuropeptides of brain origin [vasopressin and corticotropin-releasing hormone (CRF)] and pituitary origin [B-endorphin (BE) and adrenocorticotropin]. The long-term goal of these studies is to understand the effect of ethanol at each level of the hypothalamic-pituitary-adrenal axis (HPAA), with special emphasis on neuropeptide-dependent events. In earlier studies we have identified specific binding sites for CRF and BE in various rat peripheral tissues and bovine chromaffin cells in culture and established that occupancy of the CRF binding sites in rat adrenal membranes and bovine chromaffin cells and BE binding sites in hepatic membranes activate the adenylate cyclase/cAMP system. Furthermore, we have established that peripheral binding sites for CRF and BE are modulated by glucocorticoids. Exposure of rats to ethanol vapor for 14 days lowered immunoreactive plasma BE levels and reduced CRF and BE binding to a variety of peripheral tissues. In addition, chronic exposure of rats to ethanol vapors lowered pituitary CRF binding, basal and CRF-stimulated adenylate cyclase activity and pro-opiomelanocortin messenger RNA levels. Furthermore, CRF binding to rat pituitary and erythrocyte membranes was decreased following ethanol exposure. These results suggest that changes in CRF binding to erythrocyte membranes may parallel those in pituitary membranes.